A new study, performed by a research team at the United States Department of Energy’s Lawrence Berkley National Laboratory, could provide the key to understanding the role of genetics in determining human face shape. Surprisingly, it seems that the answer could lie in genetic sequences called “junk DNA.”
Enhancer Sequences a Part of Junk DNA
The paper was published in the latest issue of the journal Science, entitled Fine Tuning of Craniofacial Morphology by Distant-Acting Enhancers.
Genetics play a deterministic role in face shape, as exemplified by the similar facial features shared between parents and their children. However, the morphology of the human face is almost as distinct as a human fingerprint. Scientists have attempted to fathom the precise genetic basis for the similarity in facial morphology between siblings, particularly identical twins, whilst explaining the perceived difference between entirely unrelated individuals.
In addition, although some of the genetic defects that are involved in triggering craniofacial pathologies (e.g. cleft lips and palates) are fully understood, the genetic drivers of regular craniofacial development remain poorly understood.
Researchers working at the Berkley Laboratory have now successfully demonstrated that gene enhancers are significant players in craniofacial development. An enhancer is a short sequence of DNA that can associate with transcription and trans-acting proteins to enhance the expression of specific genes within a gene cluster. These enhancers are part of noncoding DNA stretches, known as “junk DNA,” which do not produce proteins, and much of their actions are yet to be unearthed.
Professor Axel Visel, lead researcher for the study and a geneticist working at Berkley Lab’s Genomics Division, discussed the ambiguity associated with these short stretches of DNA:
“Our results suggest it is likely there are thousands of enhancers in the human genome that are somehow involved in craniofacial development… We don’t know yet what all of these enhancers do, but we do know that they are out there and they are important for craniofacial development.”
Enhancers are either upstream or downstream of the gene they are responsible for regulating. Professor Visel claims these short enhancer sequences are akin to genetic switches.
In previous studies, Visel and his colleagues produced a map of gene enhancers in multiple organ systems, including the heart and brain. They established that these enhancers could act upon their target genes from vast distances, sometimes hundreds of thousands of base pairs away. The team wanted to see whether analogous enhancers existed for development of craniofacial features.
Enhancer Deletions Prove Link Between Craniofacial Development and Junk DNA
Working on mouse models the team used “… epigenetic profiling, in vivo characterization of candidate enhancer sequences, and targeted deletion experiments…” to investigate the relationship between craniofacial development and enhancer sequences. Catia Attanasio, lead author of the Science paper, explained that deletion of specific craniofacial enhancers led to significant variation in face and skull morphology of the mice.
Ultimately, they identified over 4,000 enhancer sequences within the mouse genome that were engaged in fine-tuning the expression of genes that influenced craniofacial development. The team characterized the function of 200 of these gene enhancers, and also made three enhancer deletions to study their impact on craniofacial development when absent.
The team then employed CT scanners to measure the precise shape and size of the skulls of the mouse models. As expected, the deletion events resulted in craniofacial alterations. The length of mouse skulls became either longer or shorter, whilst their skull widths went through similar changes.
In appreciating the intricate relationship between enhancer sequences and genes that shape face and skull morphology, alongside their pattern and location of activation within the human genome, Visel believes that scientists can achieve a better understanding of regular craniofacial morphology and development.
The lead researcher also boasts about the implications of his team’s novel research, which lays the groundwork for additional investigation. Visel suggests that his work pinpoints an area of interest for human geneticists to explore, namely enhancer-specific mutations and their role in birth defects. This could, in turn, lead to development of “… better diagnostic and therapeutic approaches.”
Speaking to BBC News, Visel maintains that certain birth defects can have a profound impact upon a child’s development. He uses cleft lips and palates – the most common craniofacial defects – to show how these aberrations can affect a child’s breathing, feeding and speech, necessitating extensive surgery to resolve.
Although the researchers have demonstrated that craniofacial development is determined by enhancer DNA stretches, the group urge further research into the area. Visel and his collaborators already plan future studies to improve their genome-wide maps, and gain a better understanding of the activity patterns of enhancer sequences.
By: James Fenner